Standard therapy for tuberculosis 1985.
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Biomedical subjects
Publications and source records attributed to P T Davidson.
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Mycobacterium tuberculosis antigen 5 is a protein antigen limited in distribution to M. tuberculosis and M. bovis and capable of eliciting typical delayed tuberculin skin test reactions in humans. A single large batch of this antigen was purified by immunoabsorbent affinity chromatography and used to skin test patients with tuberculosis and other mycobacterial infections and healthy persons in general populations in geographic areas where nonspecific tuberculin reactivity is frequently encountered. Antigen 5 was found to be no more specific as a tuberculin antigen than PPD. If the available data are accepted, then either a disparity in antigen recognition by antibody and T lymphocytes may exist or the widely accepted hypothesis attributing nonspecific tuberculin reactivity to antigenic cross reactivity with other mycobacteria may be incorrect.
A review was made of the records of 27 patients admitted to National Jewish Hospital who developed or experienced a reactivation of pulmonary tuberculosis during pregnancy or the first 12 month post partum. Sixteen patients had drug-resistant disease, and 11 had drug-susceptible disease. The drug-resistant group had more extensive radiographic abnormalities(p less than 0.01), longer sputum conversion times (p less than 0.05), and a higher incidence of pulmonary complications and death (p = 0.05). Patients with tuberculosis associated with pregnancy have the same clinical presentation as nonpregnant patients. Tuberculosis during pregnancy should be treated, and the drugs that appear to be safest for the fetus include isoniazid, para-aminosalicylic acid, ethambutol, and rifampin.
The interaction of clofazimine with M. intracellulare was studied using the in vitro dialysis model and the membrane filtration technique. With the in vitro model, clofazimine when it was inside the bag at 3 micrograms/ml or more exerted a bactericidal action within 6 days. On the other hand, when the drug concentration in the outside medium was gradually raised from 1 microgram/ml to 3 micrograms/ml over a period of 5 days, it produced only a bacteriostatic effect. Using the membrane filter technique, exposure of M. intracellulare to 1 microgram/ml of clofazimine for 24 and 48 hours induced lag periods of 24 and 168 hours respectively.
A new compound, 6 cyclo-octylamino-5,8-quinolinequinone (CQQ), a dual analogue of vitamin K and coenzyme Q, was effective against several drug-susceptible and drug-resistant strains of Mycobacterium tuberculosis. In vitro studies indicated the bactericidal nature of its action at 1 microgram/ml. Pulse exposure studies using M. tuberculosis H37Rv showed that a growth lag period of 96 hours resulted with exposure to 1 microgram/ml for 24 hours or longer.
Immunologic studies were done in a patient with common variable hypogammaglobulinemia, bronchiectasis and M. avium intracellulare pulmonary infection. Adherent cells from the patient were found to suppress the proliferative response of normal control cells to PPD antigen. The suppression seemed to be mediated by prostaglandin as it was reversed by indomethacin. Increased suppressor cell activity may play an important role in the pathogenesis of Mycobacterium avium-intracellulare infection by permitting the transformation of a status of colonization by the organism in pre-existing pulmonary conditions into an invasive, progressive disease.
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We have examined the prevalence of circulating immune complexes in sera from patients with mycobacterial infections. Sera from 68 percent of patients with active M. tuberculosis and 58 percent of patients with M. intracellulare infections had significantly elevated Clq binding activity (Clq-BA). In general there was a fall in Clq-BA with treatment. Only 15 percent of M. tuberculosis patient with a bacteriological cure, 22 percent of non-tubercular patients with chronic obstructive pulmonary disease, and 3 percent of normal individuals had an elevated Clq-BA. Antibodies to a BCG-derived antigen were demonstrated in most of the individuals studied in all groups but, significantly elevated levels were seen only in patients with mycobacterial infections. In certain patients there appeared to be an inverse relationship between Clq-BA and BCG binding, suggesting that perhaps BCG-related antigens participated in the immune complexes found. Other possible antigen-antibody complexes are discussed.
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Fourteen compounds were tested in vitro for activity against Mycobacterium intracellulare and other pathogenic mycobacteria. Only clofazimine and chaulmoogric acid showed significant activity against M. intracellulare. In view of known minimal side effects of clofazimine further studies are warranted for this drug in chemotherapy of M. intracellulare infections.
Because vitamin K is present in several species of mycobacteria, and because coenzyme Q has been found to stimulate the growth of Mycobacterium tuberculosis and atypical mycobacteria, 8 quinones that can be considered to be dual analogues of vitamin K and coenzyme Q were tested for their activity against Mycobacterium intracellulare. One compound, 6-cyclo-octylamino-5,8-quinolinequinone (CQQ) exhibited considerable activity in vitro against several strains of Mycobacterium intracellulare at a concentration of 8 micrograms per ml. It has also shown evidence of bactericidal activity against growing cultures of Mycobacterium intracellulare. Time exposure studies indicated that a minimal contact period of 24 hours with a concentration of 8 micrograms of CQQ per ml is necessary for permanent inhibitory action against Mycobacterium intracellulare. At a concentration of 1 microgram per ml, CQQ inhibited Mycobacterium tuberculosis, including the rifampin-resistant strains. The drug has no activity against rapidly growing mycobacteria or organisms that are not acid-fast.
Drug resistant mutants to streptomycin, kanamycin, viomycin, capreomycin, and rifampicin were isolated from four strains of Mycobacterium tuberculosis. The mutants isolated from each parent were then tested for evidence of development of cross-resistance to other drugs. There was no cross-resistance between either streptomycin or rifampicin and any of the other drugs. Complete cross-resistance between viomycin and capreomycin was found. Cross-resistance between kanamycin and capreomycin, and kanamycin and viomycin was variable. A review of the medical histories of 27 patients with kanamycin-resistant tubercle bacilli indicated that cross-resistance with capreomycin and viomycin occurs, but is unpredictable. Because of this variability in cross-resistance and the fact that kanamycin is a more toxic drug than capreomycin, it is suggested that capreomycin be used in the first retreatment regimen for tuberculosis when streptomycin resistance has been demonstrated.
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The clinical records of 7 patients referred to the National Jewish Hospital and Research Center over a 6-year period for evaluation of an abnormal chest x-ray and repeated sputum isolates of rapidly growing mycobacteria (Runyon's Group IV) were reviewed to determine the potential pathogenicity of these organisms. Mycobacterium fortuitum was isolated from 5 patients and Mycobacterium chelonei from 2. Haemoptysis, cough and weight loss were prominent in 6. Three had rheumatoid arthritis. Although two demonstrated cutaneous anergy, lymphocyte responsiveness to PHA was normal. PPD-F was not useful in skin testing or in the in vitro evaluation of lymphocyte function. Histologic examination of the lungs of 2 patients demonstrated caseating granulomata. One patient died of massive pulmonary haemorrhage soon after intiation of therapy. Multi-drug treatment regimens generally resulted in progressive sterilization of the sutum and improvement in the appearance of the chest x-ray. We conclude that some rapidly growing mycobacteria can cause potentially fatal cavitary lung disease and that intensive anti-tuberculosis therapy may successfully alter its course.
Two patients with Mycobacterium kansasii infection of the lung had organisms sensitive to rifampicin. Following treatment, essentially with rifampicin alone, the patients began to excrete organisms completely resistant to rifampicin. The ability of M. kansasii to acquire resistance to rifampicin during treatment has been clearly demonstrated. This reinforces the need to treat this infection with an adequate multiple drug regimen.